Project Summary The primary goal of cancer surgery is to cure patients of their tumors. One of the oncological surgeon?s greatest challenges is to successfully distinguish cancer tissue from non-cancer tissue. Fluorescence- guided surgery has radically changed the surgeon?s ability to make this determination, with demonstrably better outcomes; however, fluorescence guidance is currently only applicable in the setting of tumors that are near their parent organ?s surface, such as the throat or bladder, or cancers that are removed piecemeal, such as brain tumors. In both of these scenarios, the tumor is visualized directly with surface- based fluorescence guidance. Many cancers, such as the sarcomas that I treat in clinical practice, are removed ideally with a zone of normal tissue surrounding the tumor; this zone is referred to as the margin. This type of surgery is called a wide local excision and the success or failure of the surgery is determined by the presence or absence of cancer cells at the cut surface of the removed specimen, which is reviewed by a pathologist. The pathologist will classify the margin as positive, where cancer cells are present at the specimen?s surface?a failed wide local excision, or negative, where only normal tissue is present at the specimen?s surface?a successful wide local excision. Based on published reports, failed wide local excisions occur about 20-25% of the time, which have negative effects on patient outcomes. Applying fluorescence guidance to wide local excision surgeries holds the promise of providing real-time feedback to surgeons regarding the distance from their instruments to the tumor?s surface, thereby instructing the surgeon as to the thickness of the margin and helping avoid a failed surgery?such a change in practice would be revolutionary. Fluorescence-guided surgery for cancers requiring wide local excision is possible in theory; however, it would require that the cancer?s location be monitored via indirect, subsurface fluorescence guidance, which is not possible with current technology. I am a fellowship-trained musculoskeletal oncology surgeon, a subspecialty of orthopaedics dedicated to the surgical treatment of patients with bone and soft-tissue sarcomas that generally require radical, limb- sparing operations. I believe that fluorescence-guided surgery holds tremendous promise for treating patients with sarcomas and other cancers requiring wide local excision. I have completed seminal work to address knowledge gaps that must be filled in order to translate this concept into practice, however, I realize the limits of my knowledge and skills and understand that in order to pursue my career goals I require additional training. Through this award I will pursue mentored research and didactics in biomedical optics, advanced imaging technology, and clinical research design that will enable me to transition from a junior clinical researcher into an independent clinician-scientist and achieve my primary career goal: to facilitate meaningful and transformative research for patients with sarcoma.